Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Hellmann, Matthew D.; Nathanson, Tavi; Rizvi, Hira; Creelan, Benjamin C.; Sanchez‐Vega, Francisco; Ahuja, Arun; Ni, Ai; Novik, Jacki B.; Mangarin, Levi; Abu-Akeel, Mohsen; Liu, Cailian; Sauter, Jennifer L.; Rekhtman, Natasha; Chang, Eliza; Callahan, Margaret K.; Chaft, Jamie E.; Voss, Martin H.; Tenet, Megan; Li, Xuemei; Covello, Kelly L.; Renninger, Andrea; Vitazka, Patrik; Geese, William J.; Borghaei, Hossein; Rudin, Charles M.; Antonia, Scott; Swanton, Charles; Hammerbacher, Jeff; Merghoub, Taha; McGranahan, Nicholas; Snyder, Alexandra; Wolchok, Jedd D.

doi:10.1016/j.ccell.2018.03.018

Cited by 861 publications

(974 citation statements)

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“…In patients with previously treated SCLC, median OS was 22 months for patients in the highest TMB tertile compared with less than 4 months for all other patients [75]. In patients with previously untreated NSCLC, TMB was a predictor of response and PFS, independent of PD-L1 expression [46].…”

Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 92%

“…Currently, pembrolizumab monotherapy for patients with ≥50% PD-L1 expression is the only chemotherapysparing therapy approved for the first-line treatment of advanced NSCLC. Combination immunotherapy with a PD-1/L1 inhibitor and a CTLA-4 inhibitor in patients selected by TMB, which has no meaningful correlation with PD-L1 expression [38,45,46], has the potential to provide a chemotherapy-sparing treatment option for some patients who have less than 50% PD-L1 expression.…”

Section: First-line Treatmentmentioning

confidence: 99%

“…The rationale for using TMB as a biomarker for antitumor response is based on the concept that insertion and deletion mutations give rise to neoantigens, which in turn are determinants of tumor immunogenicity [67]. TMB has been identified as a predictor of response to immunotherapy across diverse cancers [68][69][70], including melanoma [71,72], urothelial carcinoma [73,74], small-cell lung cancer (SCLC) [75] and NSCLC [38,39,45,46]. Hellmann et al retrospectively evaluated the relationship between TMB and efficacy of combination immunotherapy with nivolumab plus ipilimumab in both patients with SCLC and those with NSCLC.…”

Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 99%

“…A current limitation in comparing TMB-related outcomes across studies in NSCLC is the lack of a universally adopted standard for the definition and determination of TMB. Both whole-exome sequencing (WES) [38,39,46] and next-generation sequencing using specific gene panels [47,48] have been used to determine TMB expressed as mutations per whole exome or mutations per megabase, respectively. In addition, the type of mutations included for the determination of TMB may vary between studies.…”

Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 99%

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Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

Kim

Shin

2020

N Engl J Med

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Nivolumab and ipilimumab, two therapeutic immune checkpoint inhibitor antibodies that block PD-1 and CTLA-4, respectively, have indications in cancer as single agents and in combination. In this Review, we examine the potential role of dual immune checkpoint inhibition with nivolumab plus ipilimumab in the management of patients with previously untreated advanced non-small-cell lung cancer, based on results from the Phase III CheckMate 227 study. Immunotherapies with indications in the first-line treatment of non-small-cell lung cancer include pembrolizumab alone and combined with chemotherapy, and atezolizumab combined with bevacizumab and chemotherapy. CheckMate 227 is the first Phase III study evaluating first-line chemotherapy-sparing combination immunotherapy and including tumor mutational burden as a biomarker for patient selection.Lung cancer is the most commonly diagnosed cancer and the leading cause of death from cancer worldwide, accounting for an estimated 18.4% of all cancer-related deaths in 2018 [1]. In the USA, lung cancer has the second highest age-adjusted incidence among primary cancer types (after breast cancer) and is associated with by far the highest cancer-related mortality [2]. Global, age-standardized incidence rates for lung cancer are lower among women than men across all regions; however, high rates among women are seen in North America, Northern and Western Europe, and Australia/New Zealand [1]. Of an estimated 222,500 new cases of lung cancer in the USA in 2017, almost half (47%) were diagnosed in women [3]. Non-small-cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases in the USA [4]. Although smoking is the most common cause of NSCLC, approximately 10-15% of patients with NSCLC have never smoked [5].Until a few years ago, the treatment for patients with advanced NSCLC with no known targetable driver mutations was essentially limited to systemic cytotoxic therapy, with platinum doublet chemotherapy as the standard first-line treatment. In randomized controlled trials, platinum-based therapies were associated with a median overall survival (OS) of 10-13 months and 2-year survival rates of 17-24% from the time of treatment initiation [6][7][8][9][10][11]. Patients who experienced disease progression during first-line therapy had few remaining treatment options, including docetaxel, erlotinib, gefitinib or pemetrexed for nonsquamous NSCLC and docetaxel, erlotinib or gefitinib for squamous NSCLC. The recent introduction of immune checkpoint inhibitors [12] has greatly improved outcomes in many cancers, including NSCLC. Therapeutic antibodies that disrupt the interaction between PD-1 and PD-L1, in other words, PD-1 and PD-L1 inhibitors, are now the preferred second-line treatment option after first-line chemotherapy [13,14]. Furthermore, the PD-1 inhibitor pembrolizumab has been approved as monotherapy for the first-line treatment of patients with advanced NSCLC and high PD-L1 expression (tumor proportional score ≥50%) [15,16]. To provide effective first-line treatment optio...

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Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 92%

Section: First-line Treatmentmentioning

confidence: 99%

Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 99%

Section: Clinical Efficacy Of First-line Nivolumab Plus Ipilimumabmentioning

confidence: 99%

See 2 more Smart Citations

Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

Kim

Shin

2020

N Engl J Med

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“…Over the past 15 years, targeted and immune‐based therapies have transformed the treatment of non–small cell lung cancer (NSCLC), driving a corresponding revolution in biomarker testing, as current guidelines recommend testing all patients with stage IV disease for actionable gene alterations (epidermal growth factor receptor [ EGFR ], ALK receptor tyrosine kinase [ ALK ], B‐proto‐oncogene Raf [ BRAF ], and ROS proto‐oncogene 1 [ ROS1 ]) and programmed cell death ligand 1 (PDL1) expression to optimize treatment selection . This year, pivotal phase 3 trials (Keynote‐189, Keynote‐407, IMpower131, and IMpower150) have reshaped frontline treatment for patients, as immunotherapy—either alone or with chemotherapy—emerges as a new frontline standard for all patients with advanced, driver‐negative NSCLC …”

mentioning

confidence: 99%

Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era

Corte

Byers

2019

Cancer

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For decades, clinicians have witnessed no therapeutic advances for small cell lung cancer, including no US Food and Drug Administration‐approved targeted therapies; recently, immune‐checkpoint blockade has emerged as a promising new option for the treatment of patients with relapsed small cell lung cancer (including recent US Food and Drug Administration approval of nivolumab in the third‐line setting) and soon may represent the frontline standard of care in combination with chemotherapy. However, there is a need to uncover biomarkers to guide patient selection and develop novel approaches to enhance response to immunotherapies.

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Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non–small Cell Lung Cancer

et al. 2020

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IMPORTANCE Robust predictors for response to anti-programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non-small cell lung cancer (NSCLC) are not fully characterized. OBJECTIVE To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020. EXPOSURES Sequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. MAIN OUTCOMES AND MEASURES Overall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status. RESULTS A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less. (continued) Key Points Question Is the copy number status of the programmed death ligand 1 (PD-L1) gene in non-small cell lung cancer associated with response to nivolumab monotherapy? Findings In this cohort study of 194 patients with non-small cell lung cancer who were treated with nivolumab monotherapy, the proportion of patients with PD-L1 amplification who achieved response was 80.0% vs 18.5% among those with PD-L1 polysomy and 17.9% among those with PD-L1 disomy. Responses among patients with PD-L1 amplification were long lasting, leading to excellent progression-free and overall survival outcomes. Meaning The findings of this study suggest that PD-L1 amplification in non-small cell lung cancer is associated with durable benefit from nivolumab trea...

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Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Cited by 861 publications

References 63 publications

Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era

Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non–small Cell Lung Cancer

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